Acute kidney injury leads to the development of tubular injury and interstitial inflammation that need to be controlled to avoid fibrosis development. We hypothesized that microRNAs (miRNAs) are involved in the regulation of the balance between lesions and adaptive repair.

Using HK2 human proximal tubular cells, we studied in vitro the response to pro-inflammatory cytokines and the regulation of miR-146a. We explored its targets in HK2 cells after stimulation by IL-1β. In vivo we explored the effect of unilateral renal ischemia-reperfusion injury (IRI) in WT or miR-146a invalidated mice.

In pro-inflammatory conditions, we identified miR-146a to be transcriptionally upregulated by ligands of the interleukin-1-toll-like receptor signaling in HK2 cells. IL-1β induced miR-146a expression in a time- and concentration-dependent manner through the activation of NF-κB, as confirmed by siRNA and luciferase reporter experiments. MiR-146a acted as a negative feedback regulator of this pathway by targeting IRAK1, thus decreasing CXCL8/CXCL1 expression by injured tubular cells. In vivo, miR-146a was found to be induced in response to IRI in a mouse model of renal unilateral IRI 7 days after the injury. In human, miR-146a was found to be induced in the renal allograft of patients who experienced acute tubular necrosis early after transplantation as compared to patients with normal allograft biopsy results (P<.05). in the renal allograft and the urine of kidney transplant recipients, and in a mouse model of renal unilateral IRI seven days after the injury. Mir-146a levels were also increased in urine samples collected ten days after renal transplantation in recipients of a deceased donor kidney as compared to recipients of a living donor kidney (P<0.01). In situ hybridization localized up-regulated miR-146a mostly in tubular cells after IRI. Fourteen days after unilateral IRI, miR-146a^-/- mice had greater tubular injury, inflammatory infiltrate and fibrosis compared with wild-type mice. Inhibition of the CXCL8/CXCL1 signaling using reparixin, a CXCR2 inhibitor, prevented the development of tubular injury, inflammation and fibrosis after IRI in miR-146a^-/- mice.

In conclusion, these results highlight miR-146a as a key mediator of the renal response to injury by limiting the consequences of inflammation, a key process in the development of acute and chronic kidney diseases.

CITATION INFORMATION: Amrouche L, Desbuissons G, Rabant M, Legendre C, Terzi F, Anglicheau D. The Fine-Tuning of CXCL8 Protects Kidney Against Ischemia-Reperfusion Injury in Mice Lacking MicroRNA-146a. Am J Transplant. 2016;16 (suppl 3).

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